This career development award will support Dr. Karen Ryan's continued training in the field of Metabolic Diseases, focusing on cardiovascular physiology and stress neurobiology, and will facilitate her transition to independence. Her long-term career goal is to be an independent academic researcher in the field of systems neuroendocrinology, with a focus on elucidating specific mechanisms linking environmental signals with the development of metabolic syndrome and cardiovascular dysfunction. Recent evidence supports depression, anxiety, and chronic stress as contributing risk factors for cardiovascular disease (CVD). This is an understudied but critical area of research, since CVD remains the leading cause of mortality in the US. In addition to chronic psychological conditions, exaggerated physiological reactions to acute stressors have also been linked to poor cardiovascular outcomes. However the specific mechanisms linking psychological stress to CVD remain unexplained, despite significant implications for understanding and treating CVD. Preliminary data demonstrate that signaling by the lipid-activated nuclear receptor, PPARgamma potently abrogated both cardiovascular and HPA responses to acute psychological stress in rats. Moreover, PPARgamma signaling blunted early neuronal activation in the paraventricular nucleus of the hypothalamus (PVH). Although PPARgamma is expressed in the PVH and other brain regions critical to the cardiovascular and hormonal responses to stress, and although PPARgama signaling is associated with improvements in indices of CVD in both rats and in humans, virtually nothing is known about the role of brain PPARgamma in the integrated stress response or in chronic stress- induced cardiovascular dysfunction. This proposal will test the overall hypothesis that CNS PPARgamma signaling is an integral part of the physiological stress response, and plays a major role to blunt cardiovascular and endocrine pathologies engendered by prolonged stress. I plan to test the overall hypothesis by pursuing three specific aims. SA1 is to test the hypothesis that activation of PPARgamma, by pharmacological agonists and/or endogenous lipid agonists, blunts cardiovascular and HPA responses to acute stress. SA2 is to test the hypothesis that activation of PPARgamma blunts the adverse systemic and cardiovascular responses to chronic variable stress (CVS). These aims, to be completed during the mentored phase, will facilitate training in new techniques. Career development activities include academic and grant-writing course-work, as well as regular meetings with the Career Advisory Committee (CAC). SA3 is to test the hypothesis that CNS PPARgamma signaling is sufficient to blunt acute responses to stress, and the adverse systemic and cardiovascular responses to CVS. This aim builds on Dr. Ryan's postdoctoral work on the brain PPARgamma system, and on the training she will receive during the mentored phase. The CAC will remain active mentors, a role that includes providing constructive critiques of Dr. Ryan's first R01 submission.